VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION AND TUMOR ANGIOGENESIS ARE REGULATED BY ANDROGENS IN HORMONE RESPONSIVE HUMAN PROSTATE CARCINOMA: : EVIDENCE FOR ANDROGEN DEPENDENT DESTABILIZATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR TRANSCRIPTS

Abstract

The hormonally regulated growth of some human carcinomas represents an important therapeutic target. We report that androgens modulate the angiogenic activity of hormone responsive human prostate cancer. To define further the critical mechanisms underlying hormone responsiveness we examined the angiogenic mediator, vascular endothelial growth factor messenger (m) RNA and protein in response to androgens in vitro as well as the angiogenic response of xenografts of human prostate cancer after androgen withdrawal in vivo. In vitro androgen deprivation of LnCaP prostate cancer cells led to decreased vascular endothelial growth factor mRNA and protein expression as well as a 5-fold destabilization in vascular endothelial growth factor mRNA transcripts. In addition, androgen withdrawal inhibited the hypoxic induction of vascular endothelial growth factor mRNA. In mice bearing LnCaP tumors castration resulted in a rapid decrease in mRNA expression and markedly reduced tumor neovascularization. These findings implicate sex steroids as an important stimulus for vascular endothelial growth factor regulation in hormone sensitive tumors and demonstrate the reversal of neovascularization after hormone withdrawal as an early event in the tumor response to therapy.